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<p>M is the most abundant structural membrane protein in coronaviruses and is essential for the formation of infectious virus particles. SARS-CoV-2 M adopts two conformations, M<sub>short</sub> and M<sub>long</sub>, and regulated transition between states is hypothesized to coordinate viral assembly and budding. However, the factors that regulate M conformation and roles for each state are unknown. Here, we discover a direct M-sphingolipid interaction that controls M conformational dynamics, interaction with other structural proteins, and virus assembly. We show M binds Golgi-enriched anionic lipids including ceramide-1-phosphate (C1P). Molecular dynamics simulations show C1P interaction promotes a long to short transition and energetically stabilizes M<sub>short</sub>. Cryo-EM structures show C1P specifically binds M<sub>short</sub> at a conserved site bridging transmembrane and cytoplasmic regions. Disrupting M<sub>short</sub>-C1P interaction alters M subcellular localization, reduces colocalization with Spike and E, and reduces virus-like particle formation and cell entry. Together, these results show endogenous signaling lipids regulate M structure and support a model in which M<sub>short</sub> is stabilized in the early endomembrane system to organize other structural proteins prior to viral budding.</p>

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Direct lipid interactions control SARS-CoV-2 M protein conformational dynamics and virus assembly

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月23日

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  • Mandira Dutta,
  • Kimberly A. Dolan,
  • Souad Amiar,
  • Elijah J. Bass,
  • Rokaia Sultana,
  • Sean M. Braet,
  • Karen J. Cárdenas-Martínez,
  • Devika Sirohi,
  • Ian K. Hicklin,
  • Richard J. Kuhn,
  • Ganesh S. Anand,
  • Gregory A. Voth,
  • Stephen G. Brohawn,
  • Robert V. Stahelin

摘要

M is the most abundant structural membrane protein in coronaviruses and is essential for the formation of infectious virus particles. SARS-CoV-2 M adopts two conformations, Mshort and Mlong, and regulated transition between states is hypothesized to coordinate viral assembly and budding. However, the factors that regulate M conformation and roles for each state are unknown. Here, we discover a direct M-sphingolipid interaction that controls M conformational dynamics, interaction with other structural proteins, and virus assembly. We show M binds Golgi-enriched anionic lipids including ceramide-1-phosphate (C1P). Molecular dynamics simulations show C1P interaction promotes a long to short transition and energetically stabilizes Mshort. Cryo-EM structures show C1P specifically binds Mshort at a conserved site bridging transmembrane and cytoplasmic regions. Disrupting Mshort-C1P interaction alters M subcellular localization, reduces colocalization with Spike and E, and reduces virus-like particle formation and cell entry. Together, these results show endogenous signaling lipids regulate M structure and support a model in which Mshort is stabilized in the early endomembrane system to organize other structural proteins prior to viral budding.